Sebetralstat fares well as oral therapy for HAE

In the phase III KONFIDENT trial, oral sebetralstat provides rapid symptom relief, cuts treatment burden, and facilitates early treatment in individuals with hereditary angioedema (HAE) attacks.

“The KONFIDENT trial met all primary and key secondary endpoints,” said Dr Marc Riedl from the University of California – San Diego, La Jolla, California, US, at AAAAI 2024. “[B]eginning of symptom relief, reduction in attack severity, and complete attack resolution were all significantly faster with sebetralstat than with placebo.”

Median time to beginning of symptom relief was faster with sebetralstat than placebo, be it with the 300-mg (1.61 vs 6.72 hours; p<0.0001) or 600-mg dose (1.79 vs 6.72 hours; p=0.0013). [AAAAI 2024, abstract L45]

Over 90 percent of attacks that reached the primary endpoint did so without a second dose or before a second dose was administered. “This means that the second dose was not necessary to achieve the primary endpoint in [most] participants,” Reidl explained.

Sebetralstat treatment also led to faster median time to reduction in attack severity (9.72 vs >12 hours; p=0.0036 [300 mg] and 7.75 vs >12 hours; p=0.0032 [600 mg]) and median time to complete attack resolution (>24 vs >24 hours; p=0.0022 and 24 vs >24 hours; p=0.0001, respectively).

“Given the unrestricted use of a second dose of oral sebetralstat in KONFIDENT, it was important to understand the proportion of attacks that achieved the primary and key secondary endpoints without a second dose,” Reidl highlighted in a press release. “What we observed was that the vast majority of attacks that successfully met the three endpoints did so with a single dose of sebetralstat.” [https://haei.org/kalvista-presents-additional-phase-3-konfident-data-at-the-2024-aaaai-annual-meeting]

Up to two doses of sebetralstat 600 mg were well-tolerated, with comparable treatment-related adverse event (TRAE) rates between sebetralstat and placebo (2.3, 3.2, and 4.8 percent for 300 mg, 600 mg, and placebo, respectively). There were no serious and severe TRAEs, nor were there any treatment-emergent AEs leading to permanent discontinuation or death.

Debilitating attacks that may be fatal

HAE is a rare genetic disorder mostly caused by deficiency or dysfunction in the C1 inhibitor (C1INH) protein (HAE-C1INH). Patients with HAE experience unpredictable, painful, and debilitating attacks of tissue swelling, which can be life-threatening once it reaches the upper airways.

Global treatment guidelines thus recommend patients to seek treatment as early as possible, consider on-demand treatment for all attacks, and always carry enough on-demand medication to treat at least two attacks, Reidl noted. However, many patients delay or withhold treatment owing to the complexities and side effects tied to currently available injectable on-demand treatments.

“Sebetralstat, a novel plasma kallikrein inhibitor, is the first orally administered therapy being investigated in a phase III trial for the on-demand treatment of HAE-C1INH attacks,” said Reidl.

This three-way crossover trial included 136 adults and adolescents with a confirmed HAE-C1INH (type 1 or 2) diagnosis and ≥2 documented HAE-C1INH attacks within 3 months. The full analysis set comprised 110 participants (median age 39.5 years, 60 percent women) and 264 attacks. Eighty-seven attacks were treated with sebetralstat 300 mg, 93 with sebetralstat 600 mg, and 84 with placebo (1–2 doses for all).

Major baseline primary attack locations were the abdomen (43 percent), arms/hands (29 percent), legs/feet (24 percent), and head/face/neck (11 percent). Other locations were the torso, genitals, and larynx/throat.

The first oral on-demand HAE Tx?

Taken together, KONFIDENT showed the potential of oral on-demand sebetralstat to treat HAE attacks rapidly, said Reidl. “The efficacy profile between the 300- and 600-mg sebetralstat dose was comparable, suggesting that 300 mg would be suitable for most patients.”

“If approved … a single dose of sebetralstat 300 mg [may] be appropriate for most HAE attacks,” echoed Andrew Crockett, Chief Executive Officer, KalVista, in a press release. “We believe that these additional efficacy and safety data only strengthen the case for sebetralstat to become the first, oral on-demand treatment available to the HAE community.” [https://haei.org/kalvista-presents-additional-phase-3-konfident-data-at-the-2024-aaaai-annual-meeting]

The 2-year open-label extension study, KONFIDENT-S, shall shed light on the long-term efficacy and safety of sebetralstat.